Molecular Profiling of Epileptogenesis: Expression and Function of Urokinase-type Plasminogen Activator and Its Receptor During Epileptogenesis

TL;DR: It was found that uPA and uPAR are induced in the rat hippocampus during epileptogenesis in areas that undergo several epileptogenic alterations, and uPA was observed to modulate neurodegeneration and neurogenesis in the mouse model of TLE.

Abstract: Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults and the epileptic process typically develops in three phases: the initial brain damaging insult [brain trauma, brain infection, status epilepticus (SE), stroke etc.], a latency period (epileptogenesis) and finally recurrent seizures (epilepsy). Epileptogenic insults are known to trigger neurobiological reorganization events in the brain such as neuronal death, neurogenesis, gliosis, granule cell dispersion (GCD), mossy fiber sprouting (MFS), rearrangement of channels and receptors and angiogenesis. Rearrangement of the brain tissue develops insidiously during the latency period or epileptogenesis phase and ultimately lead to the occurrence of seizures. The cellular alterations have been widely studied and characterized, however, the molecular alterations evoking these changes are poorly understood. In the first phase of this study, the gene-expression changes occuring during epileptogenesis and epilepsy were profiled. Next one of the highly upregulated genes was selected for more detailed studies to elucidate its expression and function during epileptogenesis. Urokinase-type plasminogen activator (uPA) was chosen as it is a part of the plasminogen system which has been implicated in various tissue reorganization events. A rat model of TLE was used, where epileptogenesis is triggered with SE, in order to analyze the gene-expression changes in different phases of epileptogenesis and epilepsy using cDNA-array technology and RT-PCR. Next, expression of uPA as well as its receptor uPAR was studied with immunohistochemical methods and enzyme activity was measured with zymography. The role of uPA in neurodegeneration, neurogenesis, and GCD after SE was evaluated using uPA deficient mice. The main results are: 1) In the normal rat hippocampus, the expression of uPA and uPAR is low. 2) After SE the expression of uPA and uPAR is increased and the most profound expression is found 1-4 d after SE. The activity of uPA becomes upregulated at 1 d and remains elevated still 14 d after SE. 3) After SE, uPA and uPAR are expressed in astrocytes, pyramidal neurons and blood vessels. uPAR is also highly expressed in hippocampal parvalbumin interneurons after SE. 4) In the mouse intrahippocampal kainic acid (KA) model, uPA deficiency does not affect acute neuronal death but promotes neurodegeneration at 20 d after SE. 5) uPA deficiency leads to a decline in hippocampal neurogenesis 20 d after SE in mice. 6) uPA deficiency does not affect GCD in the mouse brain after SE. In summary, it was found that uPA and uPAR are induced in the rat hippocampus during epileptogenesis in areas that undergo several epileptogenic alterations. Further, uPA was observed to modulate neurodegeneration and neurogenesis in the mouse model of TLE. National Library of Medicine Classification: WL 385, WL 314, QU 475, QU 450, QU 135, QU 142 Medical Subject headings: Epilepsy; Epilepsy, Temporal Lobe; Gene Expression; Gene Expression Profiling; Status Epilepticus; Urokinase-Type Plasminogen Activator; Receptors, Urokinase Plasminogen Activator; Hippocampus; Astrocytes; Pyramidal Cells; Blood Vessels; Disease Models, Animal; Rats; Mice; Mice, Knockout; Neurons; Cell Death; Immunohistochemistry